Single-cell profiling reveals age-associated immunity in atherosclerosis

作者：Virginia Smit, Jill de Mol, Frank H. Schaftenaar, Marie A.C. Depuydt, Rimke J. Postel, Diede Smeets, F.W. Verheijen, Laurens Bogers, Janine van Duijn, Robin A.F. Verwilligen, Hendrika W. Grievink, Mireia N. A. Bernabé Kleijn, Eva van Ingen, Maaike J.M. de Jong, Lauren Goncalves, Judith A. H. M. Peeters, H.J. Smeets, Anouk Wezel, Julia K. Polansky, Menno P.J. de Winther, Christoph J. Binder, Dimitrios Tsiantoulas, Ilze Bot, Johan Kuiper, Amanda C. Foks · 发表于：Cardiovascular Research · 年份：2023 · DOI：10.1093/cvr/cvad099 · 被引用次数：64 · 研究领域：Atherosclerosis and Cardiovascular Diseases、Single-cell and spatial transcriptomics、Neutrophil, Myeloperoxidase and Oxidative Mechanisms

AIMS: Aging is a dominant driver of atherosclerosis and induces a series of immunological alterations, called immunosenescence. Given the demographic shift towards elderly, elucidating the unknown impact of aging on the immunological landscape in atherosclerosis is highly relevant. While the young Western diet-fed Ldlr-deficient (Ldlr-/-) mouse is a widely used model to study atherosclerosis, it does not reflect the gradual plaque progression in the context of an aging immune system as occurs in humans. METHODS AND RESULTS: Here, we show that aging promotes advanced atherosclerosis in chow diet-fed Ldlr-/- mice, with increased incidence of calcification and cholesterol crystals. We observed systemic immunosenescence, including myeloid skewing and T-cells with more extreme effector phenotypes. Using a combination of single-cell RNA-sequencing and flow cytometry on aortic leucocytes of young vs. aged Ldlr-/- mice, we show age-related shifts in expression of genes involved in atherogenic processes, such as cellular activation and cytokine production. We identified age-associated cells with pro-inflammatory features, including GzmK+CD8+ T-cells and previously in atherosclerosis undefined CD11b+CD11c+T-bet+ age-associated B-cells (ABCs). ABCs of Ldlr-/- mice showed high expression of genes involved in plasma cell differentiation, co-stimulation, and antigen presentation. In vitro studies supported that ABCs are highly potent antigen-presenting cells. In cardiovascular disease pati...